NAVIGATOR data published in New England Journal of Medicine, and latest data from tezepelumab clinical programme presented at ATS 2021 International Conference

Tezepelumab reduced exacerbations by 77% in subgroup of patients with elevated inflammatory biomarkers in NAVIGATOR

Tezepelumab reduced exacerbations requiring hospitalisation by 85%

Detailed results from the pivotal NAVIGATOR Phase III trial showed AstraZeneca and Amgen?s tezepelumab, a potential first-in-class treatment, demonstrated superiority across every primary and key secondary endpoint in a broad population of severe asthma patients, compared to placebo when added to standard of care (SoC).¹ In one of the pre-specified exploratory analyses of NAVIGATOR, reductions in annualised asthma exacerbation rates (AAERs) were observed over 52 weeks in tezepelumab-treated patients compared to placebo when added to SoC across four patient subgroups, based on blood eosinophil count and fractional exhaled nitric oxide (FeNO) levels.^1,2?Blood eosinophil counts and FeNO levels are two key inflammatory biomarkers used by clinicians to inform treatment options and were defined as blood eosinophil count (=300 or <300 cells per microlitre) and FeNO (=25 or <25 parts per billion).^1,2 In patients with elevated baseline blood eosinophil counts (=300 cells per microlitre) and FeNO levels (=25 parts per billion), tezepelumab achieved a clinically meaningful 77% reduction in the AAER, compared to placebo.^1,2 In a separate exploratory analysis of exacerbations requiring hospitalisations, tezepelumab showed an 85% reduction over 52 weeks compared to placebo when added to SoC.^1,3 Tezepelumab also demonstrated statistically significant improvements in key secondary endpoints compared to placebo in lung function, asthma control and health-related quality of life.¹?Improvements were observed in tezepelumab-treated patients as early as week two of treatment or the first time point assessment and were sustained throughout the treatment period.¹ These results build on the NAVIGATOR data?presented?in February 2021 which showed a statistically significant and clinically meaningful⁴?reduction in the primary endpoint of AAER over 52 weeks in the overall patient population. Clinically meaningful reductions in AAER compared to placebo were observed in the tezepelumab-treated patients irrespective of blood eosinophil counts, allergy status or FeNO level.¹ Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, and principal investigator of the NAVIGATOR Phase III trial, said: ?Managing severe asthma is challenging, with multiple inflammatory pathways often contributing to the complexity of a patient's disease. These latest results underscore the potential of tezepelumab to transform treatment for a broad population of severe asthma patients, regardless of their type of inflammation.? Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: ?The reduction in hospitalisations seen in NAVIGATOR is important because patients with severe asthma have twice the risk of asthma-related hospitalisations. These results show tezepelumab has the potential to treat a broad population of severe asthma patients and to reduce the burden that this disease places on healthcare systems.? These results were published in the?New England Journal of Medicine?and will be presented this week at the American Thoracic Society (ATS) 2021 International Conference.^1-3 Further results from the tezepelumab PATHFINDER clinical trial programme will also be presented at the ATS Conference this week, including the primary analyses from the SOURCE Phase III and CASCADE Phase II trials. As previously disclosed, the SOURCE Phase III trial did not meet the primary endpoint of a statistically significant reduction in the daily oral corticosteroid (OCS) dose, without loss of asthma control, with tezepelumab compared to placebo.⁵?Data to be presented show the number of patients?that achieved a =90% reduction in OCS dose was numerically higher for tezepelumab-treated patients at 54.1% compared to 46.1% in the placebo group.⁶ In SOURCE, tezepelumab-treated patients showed improvements in exacerbations, forced expiratory volume in one second and patient-reported outcomes compared to placebo,⁶?consistent with improvements shown in pooled post-hoc analyses in OCS dependent patients from the PATHWAY Phase II and NAVIGATOR Phase III trials.^7,8?New trials are being planned to evaluate the ability of tezepelumab to reduce OCS use while maintaining asthma control in patients with chronic maintenance OCS therapy. Any new trial would aim to address unique aspects of the SOURCE trial design that may have contributed to the result of the primary endpoint. Also being presented at the ATS Conference, results from the CASCADE Phase II mechanistic trial showed that in a broad population of moderate to severe asthma patients, tezepelumab reduced eosinophils in airway tissue, compared to placebo, across subgroups of baseline blood eosinophil count, FeNO level, and allergic status.⁹?Importantly, tezepelumab was also associated with a reduction in airway hyper-responsiveness compared to placebo,⁹?which is a major hallmark of asthma irrespective of eosinophilic airway inflammation. There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups in NAVIGATOR,¹?SOURCE^6,10?and CASCADE.^9,11?The most frequently reported adverse events for tezepelumab in the NAVIGATOR trial were nasopharyngitis, upper respiratory tract infection, headache and asthma,¹?in the SOURCE trial were nasopharyngitis, upper respiratory tract infection, asthma, and bronchitis bacterial,⁶?and in the CASCADE trial were nasopharyngitis, post-procedural (bronchoscopy) complications and headache.⁹ Severe asthma Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.^12,13?Approximately 10% of asthma patients have severe asthma.^13,14?Despite the use of inhaled asthma controller medicine, currently available biologic therapies and OCS, many severe asthma patients remain uncontrolled.^13-15?Due to the complexity of severe asthma, many patients have unclear or multiple drivers of inflammation and may not qualify for or respond well to a current biologic medicine.^14-17 Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.^13,14,18?Patients with severe asthma are at an increased risk of mortality and compared to patients with persistent asthma have twice the risk of asthma-related hospitalisations.^19-21?There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.²² NAVIGATOR and the PATHFINDER clinical trial programme Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR^1,23?and SOURCE.^6,24?The programme includes an additional planned long-term safety trial, DESTINATION²⁵?and a mechanistic trial, CASCADE.^9,26 NAVIGATOR is a Phase III, randomised, double-blinded, placebo-controlled trial in adults (18?80 years old) and adolescents (12?17 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medication with or without OCS. The trial population included approximately equal proportions of patients with high (=300 cells per microlitre) and low (<300 cells per microlitre) blood eosinophil counts. The trial comprised a five-to-six-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients received their prescribed controller medications without change throughout the trial.¹ The primary efficacy endpoint was the AAER during the 52-week treatment period. Key secondary endpoints included the effect of tezepelumab on lung function, asthma control and health-related quality of life.¹ As part of pre-specified analyses, the AAER over 52 weeks was also assessed in patients grouped by baseline blood eosinophil count, FeNO level or serum specific immunoglobin E (IgE) status (perennial allergen sensitivity positive or negative).¹?These are inflammatory biomarkers used by clinicians to inform treatment options and involve tests analysing a patient?s blood (eosinophils / IgE) and exhaled air (FeNO).

NAVIGATOR endpoint: AAER in patients grouped by baseline blood eosinophil count and FeNO2

Biomarker subgroup	Results over 52 weeks Tezepelumab added to SoC versus placebo added to SoC
Blood eosinophil count =300 cells/mcl FeNO =25 parts per billion	77% reduction (95% CI: 67, 84)
Blood eosinophil count =300 cells/mcl FeNO <25 parts per billion	39% reduction (95% CI: -7, 65)
Blood eosinophil count <300 cells/mcl FeNO =25 parts per billion	53% reduction (95% CI: 33, 67)
Blood eosinophil count <300 cells/mcl FeNO <25 parts per billion	29% reduction (95% CI: 0, 50)

CI: Confidence interval

NAVIGATOR is the first Phase III trial to show benefit in severe asthma irrespective of eosinophils by targeting TSLP.¹?The?US Food and Drug Administration Breakthrough Therapy Designation?was granted to tezepelumab in September 2018 for patients with severe asthma, without an eosinophilic phenotype. SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebo-controlled trial for 48 weeks in adult patients with severe asthma who require continuous treatment with ICS plus long-acting beta2-agonists, and chronic treatment with maintenance OCS therapy. The primary endpoint was the categorised percentage reduction from baseline in the daily OCS dose, while not losing asthma control.²⁴ CASCADE is a Phase II mechanistic, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial in adults aged 18?75 years with moderate to severe, uncontrolled asthma. The primary endpoint was the change from baseline (pre-dose) to end of treatment in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies.⁹ Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in DESTINATION, a Phase III extension trial assessing long-term safety and efficacy.²⁵ Tezepelumab Tezepelumab is being developed by AstraZeneca in collaboration with Amgen as a potential first-in-class human monoclonal antibody that inhibits the action of TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is critical in the initiation and persistence of allergic, eosinophilic and other types of airway inflammation associated with severe asthma.^7,27?TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.^7,27?Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.^7,28?Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.^7,28?Tezepelumab acts at the top of the inflammation cascade and has the potential to treat a broad population of severe asthma patients regardless of their type of inflammation.^7,28 AstraZeneca and Amgen collaboration In 2020, Amgen and AstraZeneca updated the?2012 collaboration agreement?for tezepelumab. Both companies will continue to share costs and profits equally after payment by AstraZeneca of a mid single-digit inventor royalty to Amgen. AstraZeneca continues to lead development and Amgen continues to lead manufacturing. All aspects of the collaboration are under the oversight of joint governing bodies. Under the amended agreement in North America, Amgen and AstraZeneca will jointly commercialise tezepelumab; Amgen will record sales in the US and AstraZeneca will record sales in Canada. AstraZeneca?s share of gross profits from tezepelumab in the US will be recognised as collaboration revenue. In all countries outside the US and Canada, AstraZeneca will solely commercialise tezepelumab. AstraZeneca will record all sales outside of the US as product sales and recognise Amgen?s share of gross profit as cost of sales. AstraZeneca in Respiratory & Immunology Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca?s three therapy areas and is a key growth driver for the Company. AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 53 million patients in 2019. Building on a 50-year heritage, the Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Company?s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction. With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company?s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including Systemic Lupus Erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca?s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide. AstraZeneca AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca. 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